Bioactivation of Xenobiotics by Flavin-Containing Monooxygenases

Abstract

Flavoproteins are ubiquitous in nature but the ones referred to as flavin-containing monooxygenases, or simply by the acronym FMO, share a catalytic mechanism distinctly different from all other known oxidases or monooxygenases bearing flavin, heme or other redox active prosthetic groups. Like other mammalian monooxygenases, FMO’s require NADPH and oxygen as cosubstrates for the oxygenation of the third substrate but they differ in that the third substrate is not required for the generation of the enzyme bound oxygenating intermediate. Kinetic studies on mechanism (Poulsen and Ziegler, 1979, Beaty and Ballou, 1981a, 1981b) have shown that the xenobiotic substrate is not required for flavin reduction by NADPH nor for reoxidation of dihydroflavin by molecular oxygen. The latter reaction produces the 4a-hydroperoxyflavin which, in FMO, is stabilized by the protein microenvironment around the prosthetic group. The enzyme is apparently present within the cell in this form and any soft nucleophile that can gain access to the enzyme-bound oxygenating intermediate will be oxidized. Precise fit of substrate to enzyme is not necessary, and FMO catalyzes at the same maximum velocity the oxidation of compounds that possess few, if any structural features in common (Ziegler, 1988). These flavoproteins apparently discriminate between physiologically essential and xenobiotic soft nucleophiles by excluding the former rather than by selectively binding the latter. This property is largely responsible for the exceptionally broad specificity of these enzymes. Steric parameters controlling access of nucleophiles to the hydroperoxyflavin apparently differ in various forms of FMO.